As a consequence of this, DSBs are generated in the vicinity of collapsed replication forks and this activates a DDR and forces cells to undergo senescence [48 and 49]. OIS not only functions as a tumour suppressing mechanism in animal model systems [50], but also cells with features Gefitinib chemical structure of OIS, including abundant DDR foci formation, have been detected in a number of distinct benign neoplastic lesions

in humans and not in the corresponding malignant cancers [51, 52, 53 and 54••]. Given that initiation of aberrant cell proliferation in human tissues is often associated with oncogenic events, these data are strong evidence that OIS also suppresses cancer progression in humans. Some chromosomal loci, called common fragile sites (CFS), appear to be hot-spots for DSB formation as a result of DNA replication stress. These sites are usually repetitive in nature and have a tendency to form secondary structures that can impede replication fork progression [55]. In addition, CFS BGB324 order belong to chromosomal regions poor of replication origins and thus unable to cope with stalled DNA replication forks [56]. Because of their repetitive nature, sensitivity to oxidative damage, and propensity to form secondary structures (called G quadruplexes), telomeres also pose a challenge to the replication machinery. In fact, telomeres share many other features of CFS [57 and 58]. Not too surprisingly, therefore, recent results demonstrated

that oncogene expression leads to DNA replication stress, replication fork stalling, and formation of DDR foci at increased rates at telomeres [54••]. However, non-telomeric DDR foci are also generated but are resolved over a period

of several days in arrested oncogene-expressing cells. These telomeric DDR foci persist suggesting that also oncogene-induced telomeric lesions are not efficiently repaired. Does the persistence IKBKE of the telomeric DDR foci cause oncogene-expressing cells to arrest stably? In support of this, overexpression of catalytically active telomerase prevents formation of telomeric DDR foci as a result of oncogene-induced and drug-induced DNA replication stresses. Consequently, telomerase destabilizes the proliferative arrest caused by aberrant oncogene signalling [54••]. Thus, OIS is a cellular stress response that can be enforced by telomere dysfunction. Persistent telomeric DDR foci, or dysfunctional telomeres, can also be observed in most cells of benign human neoplasias and cancer precursor lesions before telomeres have become eroded. Foci form below a critical telomere length in most cells of benign human neoplasias and cancer precursor lesions such as melanocytic nevi, ductal breast hyperplasias, and colonic adenomas [54••]. Indeed, dysfunctional telomeres in cells comprising these benign lesions on average are not shorter compared to other telomeres in the same cells, supporting this conclusion.